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Camptothecin derivatives with antitumor activity

a technology of antitumor activity and derivatives, which is applied in the direction of heterocyclic compound active ingredients, biocides, drug compositions, etc., can solve the problems of hematological toxicity of lurtotecan, product accumulation in the body, and poor tumor affecting

Active Publication Date: 2010-05-13
INDENA SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is about new camptothecin derivatives that have low protein binding, good solubility, and high potency even at very low doses. These compounds have a unique structure that allows for the formation of a thiol group, which can enhance their activity. The patent describes a method for preparing these compounds and testing their cytotoxicity on tumor cells. The results showed that the sulforated derivatives were more potent than non-sulforated analogues. The compounds can also be tested for their DNA cleavage activity.

Problems solved by technology

Camptothecin, albeit endowed with wide spectrum antitumor activity, especially against colon tumor and other solid tumors and leukemias, is not used in therapy due to its high toxicity, which is particularly manifested in the form of hemorrhagic cystitis, gastrointestinal toxicity and myelosuppression.
However, Lurtotecan also has hematic toxicity.
As a consequence, the product accumulates in the body and tumors are poorly affected.
As a rule, modifications at the 5-position are considered unfavourable to the formation of the ternary complex, whereas modifications at the pyridone rings D and E have bee reported to be deleterious to the activity of the product.

Method used

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  • Camptothecin derivatives with antitumor activity
  • Camptothecin derivatives with antitumor activity
  • Camptothecin derivatives with antitumor activity

Examples

Experimental program
Comparison scheme
Effect test

example i

20-OTES-camptothecin

[0047]Camptothecin (0.100 g, 0.287 mmols) is suspended in anhydrous dimethylformamide (3 mL), under inert atmosphere, and the resulting suspension is added with imidazole (0.980 g, 1.44 mmols). The mixture is stirred for 10′ minutes, subsequently triethylsilyl chloride (TES-Cl) (0.193 mL, 1.15 mmols) is dropped therein, followed by addition of 4-dimethylamino pyridine (DMAP) (0.040 g 0.287 mmols). After 46 h, the reaction mixture is evaporated under vacuum, (TLC control of the complete disappearance of the reagent, eluent CH2Cl2 / MeOH=30 / 1). The solid is subsequently redissolved in CH2Cl2 and washed with H2O and saturated NH4Cl. The aqueous phase is extracted with CH2Cl2 (2×10 mL). The organic phases are combined and dried over Na2SO4, filtered and concentrated under vacuum, thereby obtaining the desired product (0.133 g, 0.287 mmols) as a pale yellow solid.

[0048]1H NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H, Ar, H-7), 8.25 (d, 1H, J=8.4 Hz, Ar), 7.92 (d, 1H, J=8.0 Hz, Ar...

example ii

20-OTES-Thio-camptothecin

[0049]Camptothecin 20-OTES (0.664 g, 1.44 mmols), is dissolved in anhydrous xylene (20 mL) with stirring under inert atmosphere. Subsequently Lawesson's reagent (LR), (0.523 g, 1.29 mmols) is added and the reaction is heated to 90° C. The reaction mixture is reacted for 18 h at 90° C., monitoring by TLC the disappearance of the reagent (Hexane / AcOEt=1 / 1). The solvent is evaporated off under vacuum and the residue is purified by flash chromatography (SiO2, Hexane / AcOEt=4 / 1 then 7 / 2), thereby obtaining the desired product (0.578 g, 1.21 mmol, 84%) as an intense yellow solid.

[0050]1H NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H, Ar, H-7) 8.29 (d, 1H, J=8.4 Hz, Ar), 8.03 (s, 1H, H-14), 7.97 (d, 1H, J=8.4 Hz, Ar), 7.86 (t, 1H, J=21.8 Hz, Ar), 7.69 (t, 1H, J=8.4 Hz, Ar), 6.15 (d, 1H, J=16.9 Hz, H-17), 5.62 (d, 1H, J=21.0 Hz, H-5), 5.57 (d, 1H, J=21.0 Hz, H-5), 5.34 (d, 1H, J=16.9 Hz, H-17), 1.94 (d, 1H, J=7.6 Hz, H-19), 1.90 (d, 1H, J=7.6 Hz, H-19), 1.05-0.91 (m, 12H), 0.82...

example iii

Preparation of Thio-camptothecin (IDN 6070)

[0051]20-OTES Thio-camptothecin (0.150 g, 0.314 mmols) is dissolved in anhydrous THF (10 mL) with stirring under inert atmosphere, subsequently Et3.N3HF (0.140 mL, 0.816 mmols) is dropped therein. The reaction mixture is reacted for 48 h at room temperature, monitoring by TLC the disappearance of the reagent (Hexane / AcOEt=1 / 1). The solvent is evaporated off under vacuum and the residue is purified by flash chromatography (SiO2, Hexane / AcOEt=2 / 1 then 1 / 1), thereby obtaining the desired product (0.112 g, 0.307 mmol, 98%) as an intense yellow solid.

[0052]1H NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H, Ar, H-7), 8.27 (d, 1H, J=8.4 Hz, Ar), 8.13 (s, 1H, H-14), 7.97 (d, 1H, J=8.4 Hz, Ar), 7.86 (t, 1H, J=21.8 Hz, Ar), 7.70 (t, 1H, J=8.4 Hz, Ar), 6.25 (d, 1H, J=16.9 Hz, H-17), 5.62 (d, 1H, J=21.0 Hz, H-5), 5.58 (d, 1H, J=21.0 Hz, H-5), 5.37 (d, 1H, J=16.9 Hz, H-17), 3.80 (s, 1H, OH), 1.90 (q, 2H, H-19), 1.03 (t, 3H, J=7.2 Hz, Me). 13C NMR (CDCl3, 100 MHz) δ...

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Abstract

Novel camptothecin derivatives having antitumor activity, the processes for the preparation thereof, the use thereof as antitumor drugs and pharmaceutical compositions containing them.

Description

[0001]The present invention relates to novel camptothecin derivatives having antitumor activity, the processes for the preparation thereof, the use thereof as antitumor drugs and pharmaceutical compositions containing them.BACKGROUND OF THE INVENTION[0002]Camptothecin is an alkaloid extracted from Camptotheca acuminata (Nyssaceae), first described by Wall and Wani in 1966 (J. Am. Chem. Soc. 1966, 88, 3888-3890). Camptothecin, albeit endowed with wide spectrum antitumor activity, especially against colon tumor and other solid tumors and leukemias, is not used in therapy due to its high toxicity, which is particularly manifested in the form of hemorrhagic cystitis, gastrointestinal toxicity and myelosuppression.[0003]A number of camptothecin analogues have been synthesized in order to obtain compounds having low toxicity and high solubility. At present, two drugs are used in clinical practice, namely CPT-11 and topotecan. Other derivatives, such as belotecan, rubitecan, exatecan, gima...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4375C07D491/147A61P35/00
CPCC07D491/22A61P35/00A61P35/02A61P43/00A61K31/4745
Inventor FONTANA, GABRIELEBOMBARDELLI, EZIOMANZOTTI, CARLABATTAGLIA, ARTUROSAMORI, CRISTIAN
Owner INDENA SPA
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